Muscarinic agonists
This invention relates to compounds that are agonists of the muscarinic M 1 receptor and/or M 4 receptor and which are useful in the treatment of muscarinic M 1 /M 4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1 or a salt thereof, wherein q, r, s, Q, R 1 , R 2 ′, R 2″ , R 3 and R 4 are as defined herein.
1. A method for the treatment of Alzheimer's Disease, dementia with Lewy bodies or schizophrenia in a subject, comprising administering to the subject an effective amount of a compound of the formula (1):
or a salt thereof, wherein
q is 1;
r is 1 or 2;
s is 0 or 1 where the total of r and s is 1 or 2;
Q is an azetidine linked to the adjacent six-membered ring by the nitrogen atom of the azetidine ring;
R 1 is selected from hydrogen; methyl; ethyl; fluorine oxo; and COOMe;
R 2′ and R 2″ are independently selected from hydrogen; fluorine; and a C 1-6 non-aromatic hydrocarbon group;
R 3 is hydrogen;
R 4 is hydrogen or a C 1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and
the dotted line indicates a single bond.
2. The method according to claim 1 , wherein R 4 is selected from hydrogen and methyl.
3. The method according to claim 1 , wherein the compound is selected from the group consisting of:
Ethyl 2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-(methoxycarbonyl)azetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(2-oxoazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2S)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
or a salt thereof.
4. The method according to claim 1 , wherein the compound is a pharmaceutically acceptable salt of a compound as defined in claim 1 .
5. The method according to claim 1 , wherein the compound is administered to the subject as in the form of a pharmaceutical composition comprising the compound as defined in claim 1 and a pharmaceutically acceptable excipient.
6. The method according to claim 1 wherein the moiety:
is selected from:
7. The method according to claim 1 wherein the moiety:
is selected from:
8. The method according to claim 1 , wherein the disorder is Alzheimer's Disease.
9. The method according to claim 1 , wherein the disorder is dementia with Lewy bodies.
10. The method according to claim 1 , wherein the disorder is schizophrenia.